The role of B cells in Alzheimer's disease (AD) remains poorly understood even though we and others showed their benefit as producers of antibody that help to eliminate neurotoxic beta-amyloid depositions (Ab plaques) (Olkhanud et al, Vaccine, 2011). Therefore, to understand their role in AD, we evaluated B cells in transgenic AD mice (3xTgAD mice). To our surprise, we found that B cells expressing inflammatory factors were markedly enriched in the circulation of mice with AD as compared with healthy control mice. Because we previously demonstrated that similar B cells also accumulate and promote aging-associated pathologies in aged mice and humans, we hypothesized whether these B cells are to exacerbate AD. To test this idea, we generated B-cell deficient (BKO) mice that develop AD in young and old age, 2xTgAD and 3xTgAD mice by crossing BKO mice with 2xTgAD and 3xTgAD mice, respectively. Our results revealed that AD symptoms were markedly ameliorated in both 2xTgAD and 3xTgAD mice if B cells were lost. Compared to age/sex-matched B-cell sufficient littermates, 2xTgAD/BKO and 3xTgAD/BKO mice exhibited reduced anxiety and improved memory deficits. Despite high levels of APP production in neurons, both 2xTgAD/BKO and 3xTgAD/BKO mice contained significantly fewer Ab-plaques in the brain subiculum than their age- and sex-matched littermates. The over activated microglia, another hallmark of AD pathology, in both mice without B cells was also markedly reduced. Thus, B cells appeared to play pathogenic role in AD, implying that they can be therapeutic targets for the delay of AD onset. We tested this idea in 3 different mouse models of AD, such as 2xTgAD, 3xTgAD, and 5xFAD mice by treating them with B-cell depleting antibody at the onset of the diseases. The treatment indeed significantly delayed AD symptoms in all three types of mice. Overall, our study for the first time demonstrate that B cells play pathogenic role in AD. Importantly, we also show that the AD onset can be delayed by therapeutic depletion of B cells.